Basic research of cancer therapy by improving anticancer drug sensitivity through tumor vascular remodeling

2019 Fiscal Year Final Research Report

• Project/Area Number: 17K08602
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: General pharmacology
• Research Institution: Osaka City University
• Principal Investigator: Tomita Shuhei 大阪市立大学, 大学院医学研究科, 教授 (00263898)
• Co-Investigator(Kenkyū-buntansha): 松永 慎司 大阪市立大学, 大学院医学研究科, 講師 (30704910)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Keywords: 低酸素 / がん微小環境 / 腫瘍血管 / 腫瘍免疫 / PHD阻害剤 / HIF

Outline of Final Research Achievements

The tumor microenvironment (TME) polarizes tumor-infiltrating macrophages toward tumor support. Macrophage-abundant tumors are highly malignant and are the cause of poor prognosis and therapeutic resistance. In this study, we show that the prolyl hydroxylase (PHD) inhibitor FG-4592 (FG) inhibits tumor growth of macrophage-abundant tumors and prolongs mouse survival. FG not only normalizes tumor vessels and improves tumor oxygenation but also directly affects macrophages and activates phagocytosis through the PHD-hypoxia-inducible factor (HIF) axis. Remarkably, FG can promote phagocytic ability of the Ly6Clo subset of tumor-infiltrating macrophages, leading to tumor growth inhibition. Moreover, Ly6Cneg macrophages contributed to blood vessel normalization. Using a malignant tumor mouse model, we characterized macrophage function and subsets. Altogether, our findings suggest that the PHD inhibitor can promote the anti-tumor potential of macrophages to improve cancer therapy.

Free Research Field

薬理学

Academic Significance and Societal Importance of the Research Achievements

研究の成果は、がん微小環境が造り出す腫瘍血管と正常血管の違いを明確化することにより組織再構築の分子基盤の解明に繋がると考えられる。また、PHD-HIFを基軸としたシグナルを介して形質変換した腫瘍内マクロファージがもたらす抗腫瘍効果についても同様に詳細な分子機序を明らかにする契機となる。これら研究遂行は、現在の腫瘍免疫療法では難治性を示すがんに対して、自然免疫の活性化過程を標的とした新しい腫瘍免疫療法を創出する可能性を有しており、新規創薬研究分野にも繋がることが期待される。